The current proposal is for studies on the mechanisms of myocardial protection associated with inhibition of the sarcolemmal Na+-H+ exchanger isoform-1 (NHE-1). Studies are conducted in a porcine model of whole-body ischemia induced by ventricular fibrillation (VF) in which resuscitation is either attempted using conventional closed-chest resuscitation or simulated using peripheral cardiopulmonary bypass, according to four specific aims designed to study 1) the mechanisms by which NHE-1 inhibition ameliorates ischemic contracture during resuscitation from VF, 2) the mechanisms by which post-resuscitation ventricular ectopic activity is reduced after NHE-1inhibition, 3) the late post-resuscitation effects of NHE-1 inhibition on cardiovascular and neurological function, and 4) the effects of NHE-1 inhibition when instituted before the onset of VF on subsequent resuscitation and survival. The mechanisms of ischemic contracture are investigated by measuring myocardial blood flow (fluorescent microspheres) and oxidative injury (isoprostane levels) in a closed-chest resuscitation model and by measuring myocardial Na+ and high-energy nucleotides under conditions of controlled coronary blood flow using cardiopulmonary bypass. The mechanisms of post-resuscitation ectopic activity are investigated by recording monophasic action potentials in relation to NHE-1 inhibition, Na+-Ca2+ exchanger inhibition, and sarcolemmal K+ATP channel blockade. The late post-resuscitation outcome is assess by using implantable sensors measuring blood pressure, the electrocardiogram, temperature, and mobility over a period of 7 days post-resuscitation. Finally, the effects of pretreatment with NHE-1 inhibition are compared with those when treatment is started during the resuscitation effort. Interventions that can increase outcome after onset of VF (even by a small fraction) could have a dramatic public health effect by saving thousands of lives.